Europäisches Patentamt *EP001354603A1* (19) European Patent Office Office européen des brevets (11) EP 1 354 603 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC (43) Date of publication: (51) Int Cl.7: A61K 45/06 22.10.2003 Bulletin 2003/43 (86) International application number: (21) Application number: 01271876.3 PCT/JP01/11353 (22) Date of filing: 25.12.2001 (87) International publication number: WO 02/051442 (04.07.2002 Gazette 2002/27) (84) Designated Contracting States: (72) Inventors: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU • OHKAWA, Shigenori MC NL PT SE TR Takatsuki-shi, Osaka 569-1121 (JP) Designated Extension States: • NARUO, Kenichi AL LT LV MK RO SI Sanda-shi, Hyogo 669-1535 (JP) • MIWATASHI, Seiji (30) Priority: 26.12.2000 JP 2000396220 Ikeda-shi, Osaka 563-0056 (JP) 02.02.2001 JP 2001027572 (74) Representative: (71) Applicant: Takeda Chemical Industries, Ltd. Rickard, Timothy Mark Adrian et al Osaka-shi, Osaka 541-0045 (JP) Takeda Euro IP Department, 11-12 Charles II Street London SW1Y 4QU (GB) (54) CONCOMITANT DRUGS (57) The present invention relates to a pharmaceu- tokine drug, (4) an immunomodulator, (5) a steroid and tical agent containing one or more kinds of a p38 MAP (6) a c-Jun N-terminal kinase inhibitor in combination. kinase inhibitor and/or a TNF-α production inhibitor and This combination agent is useful as a prophylactic or one or more kinds of drugs selected from the group con- therapeutic agent of the diseases such as rheumatism, sisting of (1) a non-steroidal antiinflammatory drug, (2) arthritis and the like, and other diseases. a disease-modifying anti-rheumatic drug, (3) an anti-cy- EP 1 354 603 A1 Printed by Jouve, 75001 PARIS (FR) EP 1 354 603 A1 Description Technical Field 5 [0001] The present invention relates to a combination agent of a p38 MAP kinase inhibitor or a TNF-α production inhibitor. Background Art 10 [0002] Cytokines such as TNF-α (tumor necrosis factor-α), IL-1 (interleukin-1) and the like are biological substances, which are produced by a variety of cells such as monocyte or macrophage in response to infection and other cellular stress (Koj, A., Biochim. Biophys. Acta, 1317, 84-94 (1996)). Although these cytokines play important roles in the immune response when they are present at an appropriate amount, it is thought that the overproduction is associated with a variety of inflammatory diseases (Dinarello, C.A., Curr. Opin. Immunol., 3, 941-948 (1991)). p38 MAP kinase 15 which was cloned as a homologue of MAP kinase is involved in the control of production of these cytokines and signal transduction system coupled with receptors, and there is a possibility that the inhibition of p38 MAP kinase provides a drug for treating inflammatory diseases (Stein, B., Anderson, D., Annual Report in Medicinal Chemistry, edited by Bristol, J.A., Academic Press, vol.31, pages 289-298, 1996). [0003] As compounds having a p38 MAP kinase inhibitory activity, imidazole derivatives are described in JP-T 20 7-50317 (WO 93/14081) and oxazole derivatives are described in JP-T 9-505055 (WO 95/13067), respectively. [0004] On the other hand, as thiazole compounds, the following compounds are known: 1) 1,3-thiazole derivatives represented by the formula: 25 30 wherein R1 represents a cycloalkyl group, a cyclic amino group, an amino group optionally having, as substituent (s), 1 or 2 lower alkyl, phenyl, acetyl or lower alkoxycarbonylacetyl, an alkyl group optionally having, as substituent (s), hydroxyl, carboxyl or lower alkoxycarbonyl, or a phenyl group optionally having, as substituent(s), carboxyl, 35 2-carboxyethenyl or 2-carboxy-1-propenyl, R2 represents a pyridyl group optionally having, as substituent(s), lower alkyl, R3 represents a phenyl group optionally having, as substituent(s), lower alkoxy, lower alkyl, hydroxyl, halogen or methylenedioxy, or salts thereof, which have analgesic, antipyretic, anti-inflammatory, anti-ulcerative, throm- boxane A2 (TXA2) synthase-inhibitory, and platelet coagulation-inhibitory activities (JP-A 60-58981), 2) 1,3-thiazole derivatives represented by the formula: 40 45 wherein R1 represents an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic group employing carbon as an attachment point or an amino group optionally having substituent(s), R2 represents a pyridyl group optionally substituted with alkyl group(s), R3 represents a phenyl group optionally 50 having substituent(s), or salts thereof, which have analgesic, antipyretic, anti-inflammatory, anti-ulcerative, TXA2 synthase-inhibitory, and platelet coagulation-inhibitory activities (JP-A 61-10580), 3) 1,3-thiazole derivatives represented by the formula: 55 2 EP 1 354 603 A1 5 wherein R1 represents an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a cycloalkyl group, a heterocyclic group employing carbon as an attachment point or an amino group optionally having substituent(s), 10 R2 represents a pyridyl group optionally substituted with alkyl group(s), R3 represents an aryl group optionally having substituent(s), or salts thereof, which have analgesic, antipyretic, anti-inflammatory, anti-ulcerative, TXA2 synthase-inhibitory, and platelet coagulation-inhibitory activities (USP 4,612,321), 4) a compound of the formula 15 20 25 1 2 wherein R represents an optionally substituted phenyl, R represents C1-6 alkyl or (CH2)nAr, n represents 0-2, Ar 3 4 represents an optionally substituted phenyl, R represents a hydrogen or C1-4 alkyl, R represents a hydrogen, 5 6 C1-4 alkyl and the like, R represents a hydrogen or C1-4 alkyl, R represents a hydrogen, C1-4 alkyl and the like, or a salt thereof, having an inhibitory activity of gastric acid secretion (JP-T 7-503023, WO93/15071), 5) a compound of the formula 30 35 wherein R1 represents pyridyl and the like, R2 represents phenyl and the like, R3 and R4 represent a hydrogen or 40 methyl, R5 represents methyl and the like, and R6 represents a hydrogen, methyl and the like, or a salt thereof, which is an antiinflammatory agent and antiallergic agent (DE-A-3601411), 6) a compound of the formula 45 50 wherein R1 represents a lower alkyl substituted by halogen, R2 represents pyridyl and the like, and R3 represents phenyl and the like, or a salt thereof, having an antiinflammatory, antipyretic, analgesic and antiallergic activity (JP-A-5-70446), and 7) a thiazole compound of the formula 55 3 EP 1 354 603 A1 5 wherein R represents a lower alkyl group; a lower haloalkyl group; a lower hydroxyalkyl group; a lower alkoxy(lower) alkyl group; an aralkyloxy(lower)alkyl group and the like, R1 represents a cycloalkyl group optionally substituted by 10 lower alkyl group(s) and the like, and R2 represents an optionally substituted aryl group and the like, or a pharmaceu- tically acceptable salt thereof, having a selective inhibitory activity of TNF-α production and/or IFN-γ production (JP-A- 11-49762). [0005] WO00/64894 describes that an optionally N-oxidized compound represented by the formula: 15 20 wherein R1 represents a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group 25 optionally having substituents, an amino group optionally having substituents or an acyl group, R2 represents an aromatic group optionally having substituents, R3 represents a hydrogen atom, a pyridyl group optionally having substituents or an aromatic hydrocarbon group optionally having substituents, X represents an oxygen atom or an optionally oxidized sulfur atom, 30 Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR4 (wherein R4 represents a hydrogen atom, a hydrocarbon group optionally having substituents or an acyl group) and Z represents a bond or a divalent acyclic hydrocarbon group optionally having substituents, or a salt thereof, has a superior p38 MAP kinase inhibitory activity and TNF-α inhibitory activity and is useful as a prophylactic or ther- apeutic agent for p38 MAP kinase related diseases and TNF-α related diseases. 35 [0006] Moreover, WO00/63204 describes that a compound of the formula 40 45 50 wherein a is N or C; b is CH when a is N, or O when a is C; = denotes a single or a double bond dependent upon whether the azole ring is an imidazole or an oxazole ring; 55 Z is N or CH; W is -NR6-Y-, -O- or -S-, where R6 is a hydrogen atom, C1-4 alkyl group, C3-8 cycloalkyl group, C3-8 cycloalkyl-C1-3 alkyl group, C6-18 aryl group, C3-18 heteroaryl group, C7-19 aralkyl group or C4-19 heteroaralkyl group, and -Y- is C1-4 alkylene group or 4 EP 1 354 603 A1 a bond; R2 is phenyl group, optionally substituted by one or more substituents selected from the group consisting of a hal- ogen atom, trifluoromethyl, cyano, amido, thioamido, carboxylate, thiocarboxylate, C1-4 alkoxy, C1-4 alkyl, amino, and mono- or di-C1-4 alkylamino; 5 R3 is a hydrogen atom, a halogen atom, C1-10 alkyl group, C1-4 alkenyl group, C3-10 cycloalkyl group, C3-18 hetero- cycloalkyl group, C6-18 aryl group, C3-18 heteroaryl group or -CH=N-NH-C(NH)NH2, (each of which is optionally substituted by 1 to 4 substituents selected from C1-4 alkyl optionally substituted by hydroxy, halogen atom, halo- substituted-C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, carboxy, carbonyl optionally substituted by C1-6 alkyl or C1-6 alkoxy, amino, mono- or di-C1-4 alkylamino and 5 to 7 membered N-heterocyclic group optionally further 10 containing heteroatom(s)); R5 is C6-18 aryl group, C3-18 heteroaryl group or C3-12 cycloalkyl group each of which is optionally substituted by 1 to 4 substituents selected from C1-4 alkyl, halogen, halo-substitued-C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, amino, mono- or di-C1-4 alkylamino and 5 to 7 membered N-heterocyclic group optionally further containing heteroatom(s), or a salt thereof has a p38 MAP kinase inhibitory activity and is useful as a prophylactic or ther- 15 apeutic agent of rheumatoid arthritis and the like.